MK2 limits the production of distinct acute-phase proteins by controlling the composition of gene expression modulators

When faced with a pathogenic challenge, the liver displays a strong innate immune response by producing many acute-phase proteins (APPs). APPs counteract tissue damage and regulate repair processes. They also isolate and neutralize invading pathogens and prevent further pathogen entry. The expression of APPs by hepatocytes is induced by inflammatory cytokines, which are mainly released by macrophages. Many of the molecular mediators involved here are controlled by the protein kinase MK2. However, to date it is unknown, if MK2 plays a role for hepatic APP synthesis. Therefore, the aim of this study is to reveal MK2-dependent mechanisms involved in the regulation of APP synthesis in the liver.

Upon treatment with LPS, we observed that synthesis of many APP-inducing cytokines collapses in MK2-deficient mice when compared to wildtype. Surprisingly, transcript expression of only one APP target gene, namely α2-macroglobulin was abolished. Moreover, various APPs - including hepcidin and IL-1 receptor antagonist - were even more enhanced. Further data revealed that this was mediated by IL-6 and IL-1β and occurred on the level of transcription. Our genome-wide study uncovered a pattern of MK2-dependent modulators of gene expression that ultimately limit production of APPs like hepcidin.

Conclusively, the kinase MK2 is essential for the production of many APP-inducing cytokines in the context of an inflammatory response of the organism, yet MK2 is only important for certain APPs. Most of these APPs are limited, rather than induced, in their expression due to an MK2-dependent assembly of a specific pattern of transcription factors.

Publication History

Article published online:
18 January 2023